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Spherical vesicles with a phospholipid bilayer Hydrophilic Hydrophobic Cell Membrane : Cell Membrane Uses of Liposomes : Uses of Liposomes Chelation therapy for treatment of heavy metal poisoning Enzyme replacement Diagnostic imaging of tumors Study of membranes Cosmetics Drug Delivery Why Use Liposomes in Drug Delivery? : Why Use Liposomes in Drug Delivery? Inactive: Unmodified liposomes gather in specific tissue reticuloendothelial system Active: alter liposome surface with ligand (antibodies, enzymes, protein A, sugars) Directly to site Physical: temperature or pH sensitive liposomes Drug Targeting Slide 7: Protection Decrease harmful side effects Pharmokinetics - efficacy and toxicity Changes the absorbance and biodistribution Change where drug accumulates in the body Protects drug Deliver drug in desired form Multidrug resistance Why Use Liposomes in Drug Delivery? Slide 8: Release Affect the time in which the drug is released Prolong time -increase duration of action and decrease administration Dependent on drug and liposome properties Liposome composition, pH and osmotic gradient, and environment Why Use Liposomes in Drug Delivery? Modes of Liposome/Cell Interaction : Modes of Liposome/Cell Interaction Adsorption Endocytosis Fusion Lipid transfer Classes of Liposomes : Classes of Liposomes Conventional Long circulating Immuno Cationic Liposomes Help Improve : Liposomes Help Improve Therapeutic index Rapid metabolism Unfavorable pharmokinetics Low solubility Lack of stability Irritation Custom design Lipid content Size Surface charge Method of preparation Current liposomal drug preparations : Current liposomal drug preparations Type of Agents Examples Anticancer Drugs Anti bacterial Antiviral DNA material Enzymes Radionuclide Fungicides Vaccines *Currently in Clinical Trials or Approved for Clinical Use Malaria merozoite, Malaria sporozoite Hepatitis B antigen, Rabies virus glycoprotein Amphotericin B* In-111*, Tc-99m Hexosaminidase A Glucocerebrosidase, Peroxidase Duanorubicin, Doxorubicin*, Epirubicin Methotrexate, Cisplatin*, Cytarabin Triclosan, Clindamycin hydrochloride, Ampicillin, peperacillin, rifamicin AZT cDNA - CFTR* CFTR : CFTR Gene Therapy Deliver cDNA of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to epithelial tissue of respiratory system Fuse to cell membrane and incorporate cDNA into cell Clinical trials - no significant change in symptoms Now trying adeno associated virus Cationic liposome Doxil : Doxil Chemotherapy drug doxorubin Anemia, damage to veins and tissue at injection, decrease platelet and WBC count, toxic to Treats Kaposi’s sarcoma lesions or cancer tumors Modifications of liposome “stealth” keeps doxorubin in blood for 50 hours instead of 20 minutes concentrates at KS lesions and tumors *Just approved by FDA* Amphotericin B : Amphotericin B Side effects: nephrotoxicity, chills, and fevers Systemic fungal infections in immune compromised patients Fungizone - AmB with deoxycholate AmB - kills ergosterol-containing fungal cells, also kills cholesterol-containing human cells Slide 16: No decrease in effectiveness of drug against fungi Liposomal Formulation of AmB Decrease in toxicity Exact Mechanism of liposomes not understood Cholesterol - only few %moles Phospholipid:AmB ratio Diffusion Lipid transfer Problems with Liposomal Preparations of Drugs : Problems with Liposomal Preparations of Drugs $$$$ Fungizone $40.58 Amphotec $2334 Doxil $1200 per treatment, twice the cost of normal protocol of chemotherapy and drugs Lack long term stability (short shelf life) Freeze dry and pH adjustment Low “Pay Load” - poor encapsulation Physical and chemical instability Polar drugs and drugs without opposite charge Modifications Slide 18: Possibility of new side effects Doxil “hand and foot syndrome” Problems continued Efficacy CFTR Slide 19: Studies with insulin show that liposomes may be an effective way to package proteins and peptides for use Clinical Trials for several liposomal formulations More studies on the manipulation of liposomes Future Slide 20: References Journals Allen, Theresa M. "Liposomal Drug Formulations: Rationale for Development and What We Can Expect for the Future." Drugs 56: 747-756, 1998. Allen, Theresa M. "Long-circulating (sterically stabilized) liposomes for targeted drug delivery." TiPs 15: 214-219, 1994. Allen, Theresa M. "Opportunities in Drug Delivery." Drugs 54 Suppl. 4: 8-14, 1997 Janknegt, Robert. "Liposomal and Lipid Formulations of Amphotericin B." Clinical Pharmacokinetics. 23(4): 279-291, 1992. Kim, Anna et al. "Pharmacodynamics of insulin in polyethylene glycol-coated liposomes." International Journal of Pharmaceutics. 180: 75-81, 1999. Quilitz, Rod. "Oncology Pharmacotherapy: The Use of Lipid Formulations of Amphotericin B in Cancer Patients." Cancer Control.5:439-449, 1998. Ranade, Vasant V. "Drug Delivery Systems: Site-Specific Drug Delivery Using Liposomes as Carriers." Pharmacology. 29: 685-694, 1989. Storm, Gert and Daan J.A. Crommelin. "Liposomes:quo vadi?" PSTT 1: 19-31, 1998. Taylor, KMG and JM Newton. "Liposomes as a vecicle for drug delivery." British Journal of Hospital Medicine. 51: 55-59, 1994 Slide 21: Websites James, John S. "Doxil Approved for KS." www.immunet. org.imminet/atn.nsf/page/a-235-03. Wasan, Ellen. "Targeted Gene Transfer." Member.tripod.com/~rrishna/lipos1.html "Introduction to Controlled Drug Delivery Systems." www5.bae.ncsu.edu/bae/reearch/blak… k/otherprojects/drugDeliver_97/ http://www. Mssm.edu/medicine/thrombosis/phosphol.html "Doxorubicin." http://tirgan.com/adria.htm "Clinical Pharmacology Online." http://www.cponline.gsm.com/scripts/fullmono/showmono. "Drugstore.com" http://www.drugstore.com/pharmacy/prices/Amphotec. "Sequus' Doxil Becomes First Liposome Product Approved In U.S." www.slip.net/~mcdavis/ database/doxor_1 "Liposomes." www.collabo.com/liposom0.htm Paustin, Timothy. “Cellular Membranes.”www.bact.wisc.edu/microtextbook/bacterialstructure/Membranegen.html www.cbc.umn.edu/~mwd/cell_www/chapter2/membrane.html#PHOSPHOLIPIDS Books Jones, Macolm N. and Chapman, David. Micelles, Monolayers and Biomembranes. Wiley-Liss. New York (1995). Garrett, R. and Grisham C. Biochemistry, 2nd ed. Saunders Colleges Publishing. New York (1999). 264. You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.